Synthesis and biological evaluation of novel 1-substituted 3-(3-phenoxyprop-1-yn-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amines as potent Bruton's tyrosine kinase (BTK) inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2019-01, Vol.29 (2), p.225-229
• Main Authors: Zheng, Nan, Hao, Qun, Lin, Kuaile, Pan, Jing, Li, Yingxia, Zhou, Weicheng
• Format: Article
• Language: English
• Subjects: 1-Substituted pyrazolo[3,4-d]pyrimidine; B-cell lymphoblastic leukemia; BTK inhibitors; Cytotoxicity; Inhibitory activity
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.11.051

[Display omitted] •1-Substituted pyrazolopyrimidine derivatives were designed as BTK inhibitors.•Compound 9h exhibited high potency against BTK enzyme (IC50 = 4.2 nM).•8 and 9f displayed better inhibition against B leukemia cell lines than ibrutinib.•Compound 8 has low cell cytotoxicity against normal PBMC cells. A new series of 1-substituted pyrazolopyrimidine derivatives were synthesized as potent BTK inhibitors and they were evaluated by enzyme-based assay and anti-proliferation against multiple B-cell lymphoma cell lines in vitro. Among these compounds, 9h exhibited the highest potency against BTK enzyme, with IC50 value of 4.2 nM. In particular, 8 and 9f performed better inhibition against the proliferation of B lymphoma cell lines DOHH2 and WSU-DLCL2 than the clinical drug ibrutinb. In addition, the test toward the normal PBMC cells showed that 8 possessed low cell cytotoxicity. All these explorations indicated that 8 could serve as a valuable anti-tumor agent for B-cell lymphoblastic leukemia treatment.